Myelination in the periphery involves the function of Schwann cells. A variety of diseases are associated with abnormal or disrupted myelination, ranging from primary demyelinating neuropathies like Guillain-Barre syndrome, immunological mechanisms like Chronic immune demyelinating polyneuropathy (CIDP), and additionally, implication in the etiology of neuropathic pain. The basic biology of Schwann cells and their role in myelination has been extensively studied. Nevertheless, a new influence on Schwann cell biology identified in our lab could have both basic and potentially therapeutic relevance to diseases associated with peripheral myelination: lysophospholipids, small signaling lipids that include lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), mediating their effects through specific cognate receptors that are expressed on Schwann cells. In this proposal, we will test the hypothesis that lysophospholipid signaling alters Schwann cell biology to influence peripheral myelination. Three aims will test this hypothesis: 1) Determine the role of receptor-mediated lysophospholipid signaling on Schwann cell biology and gene expression; 2) Determine the in vivo effects and receptor selectivity of lysophospholipids on peripheral nerve; 3) Determine the lysophospholipid receptor mechanisms of Schwann celI-DRG myelination in culture. Proof-of-concept studies have demonstrated that lysophospholipid receptors are "druggable" targets, raising the prospect that data from this proposal could help in the development of strategies to treat disorders of peripheral myelination